Patient Diaries As a Clinical Endpoint in Parkinson's Disease Clinical Trials

Abstract

SUMMARYParkinson's disease (PD) is the second most common neurodegenerative disorder with an estimated 4 million patients worldwide. L‐dopa is standard, and often initial, therapy for patients with this condition; however, with continued dopaminergic treatment and as the disease progresses, the majority of patients experience complications such as “wearing‐off” symptoms, dyskinesias, and other motor complications. These complications may become disabling and profoundly affect quality of life. Treatment modification and combination therapies with L‐dopa, dopamine agonists, monoamine oxidase type B inhibitors, and catechol‐O‐methyltransferase inhibitors are commonly used to manage complications. In recent years regulatory agencies, clinical researchers, and sponsors have widely accepted and utilized changes in “ON” and “OFF” time measured by Patient Hauser Diaries as endpoints for measuring efficacy of therapeutics seeking approval for symptomatic treatment of PD. Successful antiparkinsonian medications have been associated with treatment effects of more than 1 h in either reduction of “OFF” time of increase in “ON” time. Accurate “ON” and “OFF” time registration during clinical studies requires rigorous patient training. Reduced compliance, recall bias and diary fatigue are common problems seen with patient diary reported measures. Electronic diaries may help reducing some of these problems but may be associated with other challenges in large, multicenter studies.

Clinician versus machine: Reliability and responsiveness of motor endpoints in Parkinson's disease

“…Such clinical assessments have limitations imposed by various forms of bias, placebo effect (both subject and investigator), limited resolution, and poor intraand inter-rater reliability [2,11–13]. Similarly, patient-completed diaries can yield unreliable data due to inadequate compliance, recall bias, or faulty self-assessment [14]. …”

Assessing Motor Fluctuations in Parkinson’s Disease Patients Based on a Single Inertial Sensor

“…Some specific cautions were taken to ensure the validity of the diaries reported by PD patients since they are known to present some shortcomings: first, patients may not correctly identify their motor state, and, second, non-motor symptoms could provoke wrong annotations [16]. In addition, time slots might be confused and time alterations in the diary could be introduced.…”

“…Therefore, obtaining precise information on the long-term evolution of these ON-OFF fluctuations and their short-term alternations, i.e., onset and duration, is essential to provide optimal therapy to PD patients and minimise time in OFF and dyskinesias [14]. Currently, the only available method to collect such information consists of self-reporting diaries [16]. With this method, patients annotate their motor state every waking hour during 2 or 3 days.…”

“…These diaries have some important shortcomings that limit their validity and their application in clinical practice. First, they have a recall bias, and, second, they present a reduced compliance [16]. In consequence, a wearable device capable of collecting PD motor fluctuations in an objective and reliable way could help to overcome the limitations of self-reporting diaries and, in addition, would provide clinicians with a valuable tool to reduce OFF time and dyskinesia of their patients.…”

Challenges in detecting disease modification in Parkinson's disease clinical trials

“…While these questionnaires are thought to provide a global indicator of function, further work is needed to validate their usage as measure of disease progression. Patient diaries as end points in clinical trials have been associated with reduced compliance, recall bias and diary fatigue, particularly in patients with cognitive dysfunction and depression [71], and often do not correlate with quantitative objective assessments [72,73]. Stage of disease can also influence the usefulness of the questionnaires.…”